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It has been proposed that on chronic morphine treatment the micro-opioid receptor becomes constitutively active, and as a consequence, the opioid withdrawal response arises from a reduction in the level of this constitutively active receptor. In support of this, the putative micro-opioid receptor inverse agonist naltrexone has been shown to precipitate more severe withdrawal behavior in mice than the putative neutral receptor antagonist 6 beta-naltrexol. In the present study naltrexone and 6 beta-naltrexol were compared in NIH Swiss mice to test the hypothesis that their differential ability to precipitate withdrawal is due to differences in their in vivo opioid receptor antagonist potencies caused by differential access to micro-opioid receptors in the central nervous system and not necessarily by intrinsic differences in their opioid receptor activity. In naïve mice both compounds had similar potencies to antagonize morphine-induced antinociception in the hot plate and warm-water tail-withdrawal assays when measured under equilibrium conditions and afforded similar calculated apparent in vivo micro-opioid receptor affinities. In morphine-dependent mice both compounds precipitated withdrawal jumping but naltrexone was between 10- and 100-fold more potent than 6 beta-naltrexol. A similar potency difference was seen for other withdrawal behaviors. Both naltrexone and 6 beta-naltrexol at 1 mg/kg reversed antinociception induced by the long-lasting micro-opioid receptor agonist BU72 in the warm-water tail-withdrawal assay, but antagonism by naltrexone was 6-fold more rapid in onset at equal doses. Since the compounds have similar affinity for the micro-opioid receptor in vivo, the results suggest that the differences observed between the ability of naltrexone and 6 beta-naltrexol to precipitate withdrawal in the mouse may be explained by differential onset of receptor antagonist action.

A recent clinical report suggested that kappa opioids such as nalbuphine and butorphanol produced greater pain relief in women than in men. However, both compounds have been characterized as partial agonists with mixed mu/kappa opioid actions in animal studies. The aim of this study was to evaluate whether there is a sex difference in antinociception caused by nalbuphine and butorphanol as well as more selective kappa opioid agonists including U50,488 and Cl-977 in mice. In the acid-induced writhing assay, all compounds (U50,488: 1-10 mg/kg; Cl-977: 0.01-0.1 mg/kg; nalbuphine: 1-320 mg/kg; butorphanol: 0.032-0.32 mg/kg) dose-dependently inhibited writhing, but there were no sex-related differences found when comparing ED(50) values in male and female mice. In the warm water (48°C) tail withdrawal assay, U50,488 (10-100 mg/kg) and Cl-977 (0.1-3.2 mg/kg) also dose-dependently produced antinociception, although there were no sex-related differences observed. Nalbuphine (10-320 mg/kg) did not have antinociceptive effects under this condition. On the other hand, butorphanol (0.32-32 mg/kg) produced greater antinociception in male (50% MPE) than female mice (20% MPE). Further antagonist studies revealed that butorphanol is a mixed mu/kappa opioid with low efficacy. In summary, there were no sex-related differences in response to more selective kappa opioid agonists on antinociception in mice under these conditions.